Dilated cardiomyopathy is a primary disorder of the myocardium that produces cardiac enlargement with impaired systolic function, and frequently heart failure. Of the multiple causes for this pathology, increasing evidence indicates 20-35% of dilated cardiomyopathies are familial and have a genetic etiology. This project will use molecular genetic approaches to define familial dilated cardiomyopathy genes encoded at three distinct loci on chromosomes 1, 2, and 6. Positional cloning approaches and candidate analysis will be employed to define mutated genes at these disease loci. Our approaches will benefit from the close interactions with other investigators in the SCOR, whose efforts to identify pathways perturbed in heart failure should provide important clues regarding the nature of candidate genes. Project 1 will also make extensive use of the expertise and technologies provide in Cores B and C to fully elucidate the clinical spectrum of this pathology in humans. These studies will likely result in the definition of additional disease loci and the identification of other disease genes. Compilation of a full repertoire of genetic etiologies for inherited forms of heart failure and their associated phenotypes has great potential for discovering new paradigms about this poorly understood syndrome. Identification of disease genes will improve diagnosis of individuals at risk for developing heart failure which will enable longitudinal study and enable preventive interventions. More broadly, and in collaboration with Drs. Michel, Neer, Ingwall and J. Seidman, identification of gene defects that cause human heart failure will help to elucidate the cell and molecular responses of the myocyte to mutated proteins. Understanding the complex signals triggered by gene mutations should ultimately provide important insight into the molecular mechanisms for contractile dysfunction that cause heart failure incited by many other initiating events.